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MRD Negativity Is Prognostic for Survival and Maintained With Frontline Acalabrutinib/BR in MCL

Acalabrutinib plus BR prolonged duration of MRD negativity vs BR alone in previously untreated MCL, supporting the use of MRD as a prognostic biomarker.

MRD Negativity in MCL | Image Credit: © Bipul Kumar - stock.adobe.com

MRD Negativity in MCL | Image Credit:

© Bipul Kumar - stock.adobe.com


Minimal residual disease (MRD) negativity was associated with improved progression-free survival (PFS) and overall survival (OS) outcomes at the end of first-line induction therapy in patients with treatment-naive mantle cell lymphoma (MCL), according to findings from an analysis of the phase 3 ECHO trial (NCT02972840) that were presented at the 2025 EHA Congress.

The analysis also showed that patients who received triplet therapy with acalabrutinib (Calquence) plus bendamustine and rituximab (Rituxan; BR) were more likely to maintain MRD negativity vs those treated with placebo plus BR.

At the February 15, 2024, data cutoff, MRD assessment was available for 266 of 299 patients (89.0%) in the acalabrutinib arm and 252 of 299 patients (84.3%) in the placebo arm. MRD was evaluated at a threshold of 10–5 using the ClonoSEQ assay on peripheral blood every 24 weeks and at complete response (CR) or progressive disease (PD). The highest proportion of MRD negativity was observed at week 24, with 70.7% of patients in the acalabrutinib arm and 67.9% of those in the placebo arm achieving MRD negativity at this timepoint. The median time to MRD negativity was 24 weeks in both arms.

Patients who achieved MRD negativity at any point had significantly longer median PFS and OS compared with those who remained MRD positive. Specifically, patients who failed to achieve MRD negativity were 4.5-times more likely to experience disease progression.

Notably, patients who became MRD negative—regardless of clinical CR status—had improved clinical outcomes, indicating that MRD status may provide additional prognostic value beyond clinical response. Among patients who were persistently MRD positive at the end of induction or later, the median time from first MRD-positive result to progression was 20.86 months.

“In the present analysis…MRD was a stronger prognostic factor for outcome [compared with] clinical response,” lead study author Michael Wang, MD, and colleagues noted in a poster of the data.

Wang is a professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

ECHO Study Design

The ECHO trial enrolled previously untreated patients at least 65 years of age with histologically confirmed MCL who were considered fit for combination immunochemotherapy and had an ECOG performance score of 2 or lower. Eligible patients received 6 cycles of either acalabrutinib in combination with BR or placebo plus BR. BR was administered according to protocol-defined dosing schedules. Acalabrutinib was given at 100 mg twice daily.

Patients who achieved response after induction therapy proceeded to maintenance therapy with rituximab every 2 months for up to 12 doses and continued acalabrutinib or placebo until disease progression or unacceptable toxicity. Crossover from the placebo arm to the acalabrutinib arm after PD was permitted.

The aim of the present analysis was to evaluate the association between MRD status at first assessment (week 24) and the presence of baseline high-risk disease features, as well as the likelihood of conversion to or retention of MRD-negative status following initial assessment.

Key risk factors analyzed included bulky disease (stratified by that measuring ≥ 5 cm and ≥ 10 cm), TP53 mutation status, a Ki-67 proliferation index of at least 30%, and blastoid or pleomorphic histology.

Patients were stratified by their baseline MRD status, and MRD conversion was tracked throughout the study. Additional analyses explored the effect of MRD status on long-term outcomes, including PFS and OS.

The MRD-evaluable population included patients with quantifiable MRD at baseline or during follow-up; additional subpopulations were defined by MRD convertibility or persistence.

Risk Factor Analysis Findings

In the study, MRD status remained a strong predictor of PFS. Patients who achieved a CR and were MRD negative achieved the longest median PFS at 67.81 months. In comparison, the median PFS was 37.06 months in patients without a CR who were MRD negative. Among patients who were MRD positive, the median PFS was 21.91 months for those who achieved a CR and 10.18 months for those who did not achieve a CR.

The probability of maintaining MRD negativity post-induction was 2.3-fold greater in the acalabrutinib arm compared with the placebo arm (HR, 0.44; P = .022). Furthermore, maintenance of MRD negativity after initial clearance at the end of induction was associated with superior PFS outcomes. Patients who sustained MRD negativity experienced a median PFS of 70.18 months, whereas those who converted to MRD positivity during the maintenance period had a median PFS of 44.22 months (HR, 1.96; P < .0001).

A risk factor analysis identified TP53 mutation status as a predictor of MRD dynamics. Patients with TP53 mutations had a higher likelihood of remaining MRD positive at the end of induction (odds ratio [OR], 0.29; 95% CI, 0.08-1.12; P = .037). Similarly, TP53 mutations were associated with an increased risk of MRD positivity conversion after initially achieving MRD negativity (OR, 0.25; 95% CI, 0.08-0.82; P = .010).

Reference

Wang ML, Spurgeon S, Pavlovsky M, et al. Minimal residual disease with bendamustine-rituximab with or without acalabrutinib in patients with previously untreated mantle cell lymphoma: results from the phase 3 ECHO trial. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract PF882.


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